Novel Robinow syndrome causing mutations in the proximal region of the frizzled-like domain of ROR2 are retained in the endoplasmic reticulum |
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Authors: | Bassam R Ali Steve Jeffery Neha Patel Lorna E Tinworth Nagwa Meguid Michael A Patton Ali R Afzal |
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Institution: | (1) Department of Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates;(2) Division of Clinical Developmental Sciences, St. George’s University of London, SW17 0RE London, UK;(3) National Research Center, El-Tahrir Street, Dokki, Cairo, Egypt |
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Abstract: | ROR2 is a member of the cell surface receptor tyrosine kinase (RTKs) family of proteins and is involved in the developmental
morphogenesis of the skeletal, cardiovascular and genital systems. Mutations in ROR2 have been shown to cause two distinct
human disorders, autosomal recessive Robinow syndrome and dominantly inherited Brachydactyly type B. The recessive form of
Robinow syndrome is a disorder caused by loss-of-function mutations whereas Brachydactyly type B is a dominant disease and
is presumably caused by gain-of-function mutations in the same gene. We have previously established that all the missense
mutations causing Robinow syndrome in ROR2 are retained in the endoplasmic reticulum and therefore concluded that their loss
of function is due to a defect in their intracellular trafficking. These mutations were in the distal portion of the frizzled-like
cysteine rich domain and kringle domain. Here we report the identification of two novel mutations in the frizzled-like cysteine-rich
domain of ROR2 causing Robinow syndrome. We establish the retention of the mutated proteins in the endoplasmic reticulum of
HeLa cells and therefore failure to reach the plasma membrane. The clustering of Robinow-causing mutations in the extracellular
frizzled-like cysteine-rich domain of ROR2 suggests a stringent requirement for the correct folding of this domain prior to
export of ROR2 from the endoplasmic reticulum to the plasma membrane.
GenBank accession number ROR2, M97639. |
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Keywords: | |
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